ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.855T>G (p.Phe285Leu) (rs397516810)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037665 SCV000061327 pathogenic Noonan syndrome 2012-02-27 criteria provided, single submitter clinical testing The Phe285Leu variant has been reported in the literature in one sporadic incide nce of Noonan syndrome (Hung 2007). This variant has also been identified in on e individual with clinical features of Noonan syndrome by our laboratory. Addit ionally, a different nucleotide substitution (c.853T>C) resulting in the same am ino acid change has also been identified in several individuals with the clinica l features of Noonan syndrome as well as Noonan-like/multiple giant-cell lesion syndrome both in the literature and by our laboratory (Tartaglia 2002, Nystrom 2 008, Jafarov 2005, Lee 2005, LMM unpublished data). The c.853T>C variant has als o been observed to have occurred de novo in sporadic cases of Noonan syndrome. In summary, the Phe285Leu variant meets our criteria to be classified as pathoge nic. The presence of a heterozygous pathogenic variant in PTPN11 is consistent w ith a diagnosis of Noonan syndrome but this information should be reconciled wit h the complete clinical history of this individual.
GeneDx RCV000159052 SCV000208994 pathogenic not provided 2021-01-06 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 17339163, 19120036, 11992261, 28870985, 30050098, 29907801, 32164556)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587757 SCV000698083 pathogenic Noonan syndrome 3 2016-02-29 criteria provided, single submitter clinical testing
Invitae RCV000687570 SCV000815146 pathogenic Rasopathy 2018-01-23 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 285 of the PTPN11 protein (p.Phe285Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Noonan syndrome (PMID: 17339163) ClinVar contains an entry for this variant (Variation ID: 44615). A different variant (c.853T>C) giving rise to the same protein effect observed here (p.Phe285Leu) has also been reported in individuals affected with Noonan syndrome (PMID: 11992261, 23771920, 15996221, 18470943) and two different missense substitutions at this codon (p.Phe285Cys, p.Phe285Ser) have been determined to be pathogenic (PMID: 16358218, 18470943, 23321623, 21106241) indicating that this residue may be critical for protein function. For these reasons, this variant has been classified as Pathogenic.

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